Abstract
Background: Phenylbutyrate (PBA), and its metabolite phenylacetate (PAA), induce growth inhibition and cellular differentiation in multiple tumor models. However, despite their potential anti-cancer properties, several pharmacodynamic aspects remain unknown.
Methods: We conducted a dose escalating trial to evaluate twice-daily intravenous PBA infusions for two consecutive weeks (Monday through Friday) every month at five dose levels (60–360 mg/kg/day). Twenty-one patients with the following malignancies were treated: colon carcinoma 4, non-small cell lung carcinoma 4; anaplastic astrocytoma 3, glioblastoma multiforme 3, bladder carcinoma 2, sarcoma 2, and ovarian carcinoma, rectal hemangiopericytoma, and pancreatic carcinoma 1 each.
Results: Conversion of PBA to PAA and phenylacetylglutamine (PAG) was documented without catabolic saturation. Plasma content of PBA ≥1 mM was documented for only 3 h following each dose at the top two dosages. The therapy was well tolerated overall. Common adverse effects included grade 1 nausea/vomiting, fatigue, and lightheadedness. Dose limiting toxicities were short-term memory loss, sedation, confusion, nausea, and vomiting. Two patients with anaplastic astrocytoma and a patient with glioblastoma remained stable without tumor progression for 5, 7, and 4 months respectively.
Conclusions: Administration of PBA in a twice-daily infusion schedule is safe. The maximum tolerated dose is 300 mg/kg/day. Study designs with more convenient treatment schedules and specific molecular correlates may help to further delineate the mechanism of action of this compound. Future studies evaluating PBA's ability to induce histone acetylation and cell differentiation alone or in combination with other anti-neoplastics are recommended.
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Acknowledgments
The authors would like to acknowledge the support and guidance of Jamie Zwiebel, MD at the Clinical Investigational Branch; Cancer Therapy Evaluation Program at the National Cancer Institute, Bethesda, MD.
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This work was supported in part by grant UO1: CA69856 from the National Cancer Institute, Bethesda, MD (Memorial Sloan-Kettering Cancer), and a Clinical Cancer Research Grant from the Cancer and Leukemia Group B (LHC).
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Camacho, L.H., Olson, J., Tong, W.P. et al. Phase I dose escalation clinical trial of phenylbutyrate sodium administered twice daily to patients with advanced solid tumors. Invest New Drugs 25, 131–138 (2007). https://doi.org/10.1007/s10637-006-9017-4
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DOI: https://doi.org/10.1007/s10637-006-9017-4